No solubility problems with OSM-S-35, an average IC50 of 30 nM (now measured 3 times), good glutathione data however zero effect in mice.

Previously, an assumption was made that the near neighbours were so insoluble, this would have explained the lack of activity. With the potent new NN compounds we can no longer assume this.

Analysis of potency vs logP for the set:

https://plus.google.com/114702323662314783325/posts/J8LdunS2uQ8

2. Glutathione trapping experiments on OSM-S-35

In earlier rounds of biological evaluation, the near-neighbours showed extremely high potency. One concern regarding this family of compounds, was their ability to act as Michael acceptors in vivo. A glutathione trapping experiment performed in Sue Charman’s lab suggests that the compounds do not act as Michael acceptors. Do these results validate our continued interest in this family? Should we continue to synthesise analogues? MNR and AEW can highlight current synthetic challenges. Or should we progress one or two more polar compounds into in vivo?

Glutathione data

http://malaria.ourexperiment.org/biological_data/6729

The NN compounds also showed high potency in a late stage gametocyte assay. Should we re-evaluate some of these in such an assay to confirm their activity?

Original gametocyte data:

http://malaria.ourexperiment.org/biological_data/3066

3. The Wanted Compounds

MNR performed modelling to decide whether further synthetic efforts should be directed towards the synthesis of some compounds identified at an earlier stage of the project.